Progression/progress

Progress, from the Latin progressus, can be defined as "a movement toward a goal or to a further or higher stage." The word generally has positive connotations. If we hear that progress is being made in the fight against cancer, for instance, we regard this as a good thing.

A synonym for progress is progression.

Many people, myself most definitely included, associate the word "progression" with cancer, and in that context, progression, unlike progress, is a decidedly negative term.

(Note: this interesting relationship between the words progress and progression was put into my mind by a widow friend I've been having some very interesting discussions with. It's good to have people like that to talk to, other people who really "get it.")

Earlier today, I saw in my Twitter feed an article from the Journal of Clinical Oncology with an amazing result that brought me to the verge of tears.

The title of the article is Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP. You can see the whole thing yourself at that link if you feel up to wading through dense scientific prose. Here, I'll provide an explanation and summary of the key findings and how they relate to my dearly departed wife.

Alectinib is something I'm very familiar with. It's a drug that Cara took for about six months, from late 2013 to mid 2014, as part of a clinical trial. The article is also about a clinical trial of alectinib, but a different one from that in which Cara was enrolled.

Alectinib is an inhibitor of the ALK protein; a rearrangement of the gene encoding that protein is what drove the growth of Cara's lung cancer (hence, "ALK-positive.") The first FDA-approved ALK inhibitor drug was called crizotinib. That was the first drug Cara received after being diagnosed. As I wrote in a previous blog entry, "Being a scientist, I had naturally looked up research articles about crizotinib, and had seen that, in the clinical trial, the median progression-free survival [and there's that word - progression] was about 8 months longer with crizotinib than with traditional chemotherapy. This meant that the typical outcome for someone taking crizotinib was that they would gain about 8 months in which their disease would be under control, but ultimately they would still die of lung cancer."

For Cara, progression on crizotinib occurred after only two months. Bad luck, much worse than average. Why? We'll never know. But after crizotinib stopped working, and after Cara underwent a surgery that brought her back from near death's door by draining a massive accumulation of fluid from around her heart, and after her condition stabilized, she started a clinical trial for alectinib, a newer ALK inhibitor drug. The title of that clinical trial was An open-label, non-randomized, multicenter phase I/II trial of RO5424802 given orally to non-small cell lung cancer patients who have ALK mutation and failed crizotinib treatment. As you can see from the title, it was a trial specifically for people who had already taken crizotinib and for whom crizotinib had stopped working.

I've just looked up the results of that trial for the first time on the ClinicalTrials.gov website. The median progression-free survival is listed as 7.5 months. So again, Cara did worse than the average patient, but not to as great an extent.

To summarize, the typical outcome for someone who was diagnosed with ALK-positive lung cancer, put on crizotinib until it failed, and then put on alectinib until it failed, would be that within a year and a half, both drugs would have stopped working, and then it would be time to move on to still other treatments. Until ultimately (in most cases) all treatments fail and death occurs.

That's still significant progress from the previous status quo. I remember well, after being told that it looked like Cara had lung cancer, sitting there in the hospital's surgery waiting area and looking up lung cancer survival statistics on my laptop, and reading that the median life expectancy for someone diagnosed with stage IV lung cancer was only 8 months. Cara lasted 20 months. If not for the heroic work of research scientists in discovering the ALK driver mutation and developing treatments targeting it, that probably would have been less than 8.

But now, given all that background information, let's return to the article that so shook me today. The study in that article was of alectinib as a first-line ALK inhibitor - that is, the patients had not previously received crizotinib or any other ALK inhibitor. And here's the thing - cancer that has evolved to become resistant to crizotinib, even if it's not yet resistant to alectinib, could very well be closer to developing that resistance. So the median progression-free survival in the study of alectinib for ALK-inhibitor-naive patients?

At the three-year followup point, it had not yet been reached.

62% of the patients had not had disease progression after three years. 78% of patients were still alive after three years.

Cara was diagnosed three years and seven months ago. The two-year anniversary of her death is fast approaching.

There are other advantages to alectinib. Unlike crizotinib, it can cross the blood-brain barrier and treat brain metastases. Cara, like many lung cancer patients, developed metastases in her brain, and had to undergo radiation therapy for them. (Fortunately, they never grew large enough to significantly affect her quality of life - although the steroids she took to reduce swelling while undergoing the radiation therapy had some nasty side effects. I remember being woken by her crying in pain from horrible cramping in her calves.) As well, although the specific side effects of specific drugs vary from patient to patient, in Cara's case (and I know she wasn't alone in this) alectinib had by far the least adverse side effects of any of the treatments she received. Alectinib was so effective (until a small spot of disease on her liver evolved to become resistant to it) and its side effects so minimal that for a little while it seemed Cara was almost back to her normal self!

I write all this in the hopes that it will be educational, that people will gain a little bit better understanding of what goes into the fight against cancer, both from the patient perspective and the research scientist perspective. I also write in the hopes of persuading. Cancer research is so important. Great progress has been made in our efforts to control disease progression, but we have a long, long way to go.

What can you do, today, to help?

I'll suggest two things.

One: help promote lung cancer awareness and research funding. One way to do this is to sign up for and/or donate to Team Cara in the Breathe Deep Cleveland event that Cara helped found before she passed away. I've written before about the shocking statistics for lung cancer research: it only gets about 1/15 the federal research funding per patient death as breast cancer research. This needs to change.

Two (and sadly, this is probably far more important right now): speak out in any way you can against Trump's proposed budget and its massive cuts to the NIH. Call your elected officials, write letters to the editor, tell your friends. Use personal examples. This article that just came out is one perfect example of the importance of funding medical research. If such research was better funded, the critical discoveries might have been made sooner, and Cara might still be alive. Conversely, if more cuts are made, a lot of potentially life-saving studies will be shut down. Let's not let that happen.

Breathe Deep Cleveland

On April 1 of this year, Cara wrote the following in her blog:

I can't believe we're less than two months away from the Breathe Deep CLE event, it's surreal.

Okay, I'm going to pause here for a moment because I just noticed that Cara made a little mistake - she should have said "less than three months," not "less than two months." It might seem weird that I'm nitpicking this, but it just really stands out to me due to the fact that Cara passed away slightly more than two months before the event - hence we could not have been "less than two months away" while she was still alive to write about it. What's weird is that I selected this passage to be read at her funeral, and I didn't notice the error at the time. And I'm usually so good about spotting things like that. I guess my mind was not quite fully functional that week! Anyway, back to Cara:

I have such high hopes for this thing. We have 15 people signed up and a good chunk of money raised already but we need more. I want this thing to be EPIC. I know it has the potential to be - if you think about how many people are impacted by lung cancer in some way - or hey, even cancer in general... Come give us a shout out. Walk a few miles (you can borrow my shoes, if you want!) and eat a bagel. Hug someone, ask questions, learn things. It'll be fun. My hopes are so, so high.

Remember what happens on this episode of Saved by the Bell? Well don't worry, I'm not going to go on a speed bender and break down in Mark Paul Gosselar's arms (unless he's available?). I'm just a little scared. I'm afraid of failure. I'm reminded of a time when I had a birthday party and only two people came. One of those people stole some of my presents. Why was I friends with her, again? Never mind.

It has to succeed, it just has to. I'm not saying this because my name is all over it - I just want people to come out, take a walk, and learn things. Understand what a huge impact lung cancer has on us all.

Cara poured her heart and soul into this event. I'm so proud of her for recognizing the importance of having such an event here in Cleveland, reaching out to the national LUNGevity Foundation to get the ball rolling, and then putting in all the time and effort with the planning committee to make it a reality. Not to mention the work she did in promoting the event and designing the logo for her fundraising team.

All this while battling stage IV lung cancer.

Thanks to the efforts of numerous people, but Cara most of all, the event was, indeed, a success. It raised over $39,000, smashing the original goal of $26,000. Cara alone raised over $13,000. Although it would have been an undeniable success for the fundraising alone, there was some doubt that the event would even take place. We have had a strange summer weather-wise, and June 26 was part of a stretch of nearly two weeks in which it rained almost every day. That day was one of the rainiest of them all. The night before the event, an email was sent out to all participants: Breathe Deep Cleveland would be held rain or shine, but if there were thunderstorms in the area, it would have to be canceled. The weather forecast at the time did indicate a significant chance of thunderstorms.

I can just imagine how nervous Cara would have been, how dismayed she would have felt if the event she had worked so hard for had had to be called off.

Fortunately, there were no thunderstorms. I was a volunteer as well as a participant for the event, and as we were setting things up and then getting people checked in it was almost continuously raining, reaching torrential downpour status at times. The weather certainly depressed turnout - from 250 registered participants, about 100 people actually showed up. Things went very well, though, all things considered. And luckily, for the actual walk/run portion, the rain mostly stopped.

Before the walk/run started, there was a Zumba warmup, which many people still participated in despite the rain. Then we had several speakers. The first was Cleveland councilman Joe Cimperman. I'm grateful to him for taking the time to speak, but it occurred to me that Cara would have disliked his speech, because literally everything he said was related to smoking reduction efforts. Now, realistically, that is a very important way to reduce lung cancer mortality. However, to focus entirely on that aspect - "he's feeding into the stigma," I can imagine Cara saying. She hated the stereotype that lung cancer is only a smoker's disease. She hated how so many people, upon learning that she had lung cancer, would ask before anything else whether she had smoked. Cara thought that was a question that only really needed to be asked by a patient's doctor.

Cara's doctor, Nathan Pennell, was another speaker at the event, and gave some nice remarks about promising new efforts to fight this awful disease. Cara had envisioned that she would give a speech there. I wish I could have heard her speech. I'm sure it would have been fantastic. As we all know, she was excellent at both writing and at talking to people. Despite standing just 5'2", she had a commanding presence. I hope that I was able to live up to her by speaking in her stead. I'll share my remarks here:

First, I want to thank you all for being here today. Cara McManus, my wife, was the person who took the initiative in creating this event. Many of you knew Cara, but there are also a lot of you here who did not know her in person. I want to say a few words about Cara and about why this cause is so important.

Cara was a very active person whose favorite thing in the world to do was ride her bicycle. In the spring of 2013, she started to have some issues with wheezing and shortness of breath. The first time she went to see a doctor, they said that it was probably asthma and gave her an inhaler. No one would ever guess that a healthy 34-year-old with no history of smoking would have lung cancer. The doctor was wrong, of course – it wasn’t asthma. But throughout that summer, even as Cara’s symptoms did not improve and then gradually worsened, she continued to pursue her active lifestyle. In August, she did a two-day, 150 mile MS charity bike tour. The truly amazing thing is that, despite all the issues she had been having, she said that she felt fantastic on that ride.

Three weeks later, she was hospitalized and diagnosed with stage IV lung cancer.

During Cara’s battle with cancer, we saw firsthand the benefits of groundbreaking research. She ultimately lived 20 more months after her diagnosis. If the same thing had happened to her five years sooner, it’s likely she would have survived for only a fraction of that time. We had the opportunity to make so many happy memories together during the extra time afforded by those new treatments. And she even got to go on a lot of bike rides last year.

Cara became very passionate about the cause of lung cancer awareness and research funding. In this country, we make such a big deal about breast cancer awareness. Now, I’m not knocking breast cancer awareness. It’s a very important issue. But why, Cara wondered, couldn’t there be a similar movement for lung cancer? Lung cancer kills more people than the next three top cancers combined. 27% of all cancer deaths are due to lung cancer, yet lung cancer gets only 6% of federal research funding.

As Cara sadly realized, this is in large part due to the stigma of lung cancer being considered a smoker’s disease. But the truth is, lung cancer can happen to anyone, even someone like Cara who was healthy and never smoked. And even if someone did smoke, it doesn’t mean they deserve to die of cancer.

Cara founded this event because she saw the urgent need to raise awareness around the issue of lung cancer and to increase the funding toward more groundbreaking treatments and earlier detection. Perhaps if lung cancer research was funded in proportion to the deaths this disease causes, or perhaps if doctors didn’t assume that there was no way a young non-smoker could have lung cancer, then Cara, instead of me, might be the one standing up here talking to you right now.

She’s not. But there are so many people out there who are or will be going through the same thing. That’s why it’s so important that this cause succeeds. I’ll never forget Cara’s passion for this cause, and I hope none of you will either.

This year was the first annual Breathe Deep Cleveland. We intend to make it bigger and better in the future, and we anticipate nice weather next year!